Colton Nielson

Demise of the Mind: Alzheimer’s Disease

Today’s Roadmap of Alzheimer’sGeneral IntroductionHistory/FactsRisk FactorsThe 3 StagesMechanisms of Alzheimer’sDrugsThe cutting edge: Cure?

First discovered by Dr. Alois Alzheimer in 1906

Alzheimer’s disease (AD) is an irreversible, progressive brain disease that slowly destroys memory and cognitive skills, and eventually results in death of the patient

Complex neurodegenerative disorderIncreasing age is the greatest risk factor Probability of occurrence doubles every 5

years after the age of 60

What is Alzheimer’s Disease?

A breakdown of Alzheimer’s DiseaseCurrently 7th leading cause of death in U.S.Estimated U.S. economy dollar losses of

$1.75+ trillionCost of annual patient care in U.S. is $100+

billionAnnual costs of Alzheimer’s Stricken patient

in U.S. is $40,000 + Effects 37 million people worldwide

AgeLow mental ability in early lifeReduced mental and physical activity in late lifeHead injuriesVascular diseases: hypertension and

atherosclerosis, smoking, obesity, and diabetesDecreased reserve capacity of the brain

Reduced brain sizeLow educational and occupational statusDown’s Syndrome or other forms of mental

retardation

Predisposed Risk Factors

Scientists have debated the number of differentiable stages-today, three is widely accepted number

The Three Stages of Alzheimer’s Disease

Typically lasts 2-4 years leading up to and including diagnosis

Symptoms: recent memory loss that can effect job performance

Examples include:Getting lost on the way to

workTaking longer with routine

choresTrouble handling money

or paying bills

Stage 1 of Alzheimer’s Disease

Duration of 2-10 yearsSymptoms include: increasing

memory loss and confusion with a shorter attention span

Examples of Stage two Alzheimer’s:Problems recognizing close

friends and familyProblems finding the right

wordsRapid swing s in body weightNecessity of full-time

supervision

Stage 2 of Alzheimer’s Disease

Terminal StageDuration of 1-3 yearsSymptoms include: inability to

identify family members or themselves in a mirror

Examples: rapid weight lossLoss of interest in self careLoss of communicationLoss of control of bowels and

bladder

Stage 3 of Alzheimer’s Disease

Only way to diagnose is autopsy of the brainThere are several diagnostic methods

Physicians performtake a detailed patient historyTake a past family medical historyPhysical and neurological examinationsNeuropsychological testing-measure memory,

language, simple math skillsCT scans or MRI tests which can detect strokes

or tumors or changes in brain structure that suggests early signs of AD

Diagnostic Methods

Two forms: familial and sporadic Familial-autosomal dominant disorder with

early onset1st mutation causing familial found in amyloid

precursor protein (APP) gene on chromosome 21

Most mutations are in the homologous presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes

Familial is uncommon: occurrence rate well below 0.1%

Genetics Behind Alzheimer’s Disease

Genetics Behind Alzheimer’s DiseaseSporadic disease linked with apolipoprotein E

(APOE)Heterozygotes for the APOE allele experience

3x the risk of developing the disease compared

to individual withoutHomozygotes increase risk of disease over

15xMechanism: APOE allele modifies age of

onset-each allele lowers age of onset of disease by 10 years

Get diffuse cerebral atrophy with widened sulci and enlarged ventricles

Destruction of nerve synapses has been linked with correlation of cognitive decline

Lesions occur and neurons are further destroyed

What happens within the Brain

Plaques are known as microscopic clumps of a protein called beta-amyloid peptide and tangles are twisted microscopic strands of the protein tau.

Believed beta-amyloid may directly interact with tau to accelerate formation of neurofibrillary tangles.

Beta-amyloid activates inflammatory response from brain

Physiology of the Brain

Amyloid-Beta PP is type-1 transmembrane proteinCleaved by two proteases (beta and gamma

secretases) to from Amyloid betaAmyloid beta occurs normally in plasma and CSFMismetabolism of Amyloid-beta PP is believed to

initiate event that leads to aggregation of Amyloid-betaStrong evidence in favor of hypothesis: Extra

Chromosome 21 in Down’s Syndrome, which contains the Amyloid beta PP gene, leads to increased synthesis of Amyloid beta PP and early onset of Alzheimer’s disease

A Hypothesis Behind Alzheimer’s Disease

Post-mortem studies show reduced uptake and reduced release

Without this critical neurotransmitter, memory loss associated with the onset of Alzheimer’s Disease is observed

many symptoms of dementia explainedThere was false hope that restoring

cholinergic balance by AchE inhibitors would reverse progression

Still main target used today

Problems with Acetylcholine

1993-FDA approved as first Alzheimer drug

Studies-delay institutionalization up to 1 year-reduce costs up to $3.6 billion annually

Estimated lifetime savings of $10,000

Tacrine (Cognex)-The first Cholinesterase Inhibitor

Unfortunately, associated with sever hepatotoxicity

Affected its permeability-often eliminated too soon or too late

Induced variable drug amounts in body

Attributed to poor selectivity for AchE as also binds butyrylcholinesterase

Lead to 2nd generation drugs

Tacrine-The Other Side of the Story

Can cross the BBB with nearly 100% efficiency-approved for all stages of treatment

Highly selective reversible inhibitor of AchE

Unaffected by foodLong plasma half-life of 70

hours-administered once dailyMost widely used across the

worldReduced Side effects

Donepezil (Aricept)

Cognition advantages up to 1 year

Donepezil (Aricept)

Although short half life of 2 hours, cholinesterase inhibition in brain last up to 10 hours

Therefore, identified as pseudo-irreversible inhibitor of AchE and BuchE

Short half life leads to 2x daily dosing

Rivastigmine (Exelon)

Isolated from Galanthus woronowii

Competitive and reversible AchE inhibitor

Much less potent than Tacrine against BuchE

Drug acts directly on nicotinic receptors increasing release of acetycholine

Short half life of 8 hours-2x daily

Galantamine (Reminyl)

2003-released onto market.NMDA (N-methyl-D-asparate)

receptor antagonistregulates activity of glutamate-

chemical messenger involved in learning and memory

Up until now-drugs weren’t neuro-protective and only enhanced cognitive state

Protects brain cells against excess glutamate-released by damaged cells of patients

Memantine (Ebixa or Namenda)

Diseased brain-attachment of glutamate to NMDA receptors permits calcium to flow freely into cell

Over time-leads to chronic overexposure to calcium which speeds cell damage

Memantine slows progress of disease up to 1 year

Memantine (Ebixa or Namenda)

Oral route long preferred Alzheimer’s drugs associated with “first-

pass” metabolism-leads to reduction in bioavailability of medications

Recent studies show greater patient cooperation with transdermal route, buccal, and nasal routes

All Alternative ways to deliver a drug to CNS without associated oral administration side affects

Drug Administration

Alzheimer’s lower in countries with low fat and calorie diets

Essential fatty acids-improvement in mood and mental function than placebo

Vitamin E depletion in patient-2000 IU daily can delay onset

Vitamin C in synergy enhanced effectsThiamine (B1)-marked improvements in

mental function and assessment scoresVitamin B12 and Melatonin also show

potential

Alternative Treatments to Alzheimer’s Disease

Amyloid Protein: beta-secretase and gamma-secretase

Tau protein-main ingredient of tangles-other hallmark abnormality

Anti-inflammatory drugsInsulin release

Future Drug Targets

Within 3-4 years, next generation of drug therapy expected to reach the market.

Scientists have discovered how the beta-amyloid protein fragment is clipped from its parent compound amyloid precursor protein (APP) by two enzymes: beta-secretase and gamma-secretase

HUGE area of research-develop medications aimed at every possible point in amyloid protein

Especially these two enzymes

Future Drug Targets

Tau Protein: main ingredient of tangles-other hallmark brain abnormality

Researchers are attempting to develop drugs that bind tau molecules

Want to keep them from collapsing and twisting into tangles-destructs critical cell transport mechanisms

Anti-inflammatory drugs will attempt to offset inflammation response caused by the disease

Future Drug Targets

Reduced glucose utilization and energy metabolism occurs early in the course of Alzheimer’s Disease-correlates with impaired cognition

Regulated by insulin and insulin growth factor 1 (IGF-1)

Reduced levels of insulin and IGF-1 polypeptide genes found in advanced Alzheimer’s disease patients

In frontal lobe-progressively reduced levels of mRNA corresponding to insulin, IGF-1, and IGF-2 polypeptides and their receptors, and tau were found as the disease advanced

A Bright Future: Insulin

Nitrosamines formed by chemical reaction between Nitrites or other proteins

Nitrates and Nitrates-found in cured meats, cheese products, as well as beer and bottled water

Generated under strong acid conditions-stomach or from broiling or frying foods

Can prevent by removing sodium nitrite content in food

A Bright Future: Nitrosamines

Strong parallels between age-adjusted increases in death rate from Alzheimer’s in human exposure to nitrates, nitrites, and nitrosamines

Nitrosamines found in preserved foods as well as fertilizer

Society has moved to diet rich in amines and nitrates-leads to increased nitrosamine production

Increased exposure-caused both to processed foods and crops leeching nitrates from the soil and contaminating water supplies used for crop irrigation

A Bright Future: Nitrosamines

Become reactive at cellular level-changes gene expression and leads to DNA damage

The changes induced by nitrosamines are similar to those of aging, as well as Alzheimer’s Disease

Produce biochemical changes inside cells and scientists are beginning to believe Alzheimer’s could be caused by nitrosamines found in processed foods, and water

Nitrosamines: Mechanism of Action

Cascading basic science, genetic, and clinical evidence supports key role of the inflammatory cytokine, TNF, in the pathogenesis of Alzheimer’s Disease

Inflammation of the brain long known as a strong contributor to Alzheimer’s Disease

A Bright Future: Inflammation

http://nrimed.reachlocal.net/videos/dementia-patient-recognizes-wife-after-inr-treatment/

Wilkinson, David . "Pharmacotherapy of Alzheimer's disease." Psychiatry 4.1 (2005): 43-47. Print.

Alzheimer's Association. "The Journal of Alzheimer's Association." 2010 Alzheimer's Facts and Figures 1st ser. 6.2 (2010): 158+. Print.

Readings

List the 4 FDA approved Alzheimer’s Disease drugs and draw their structure

These FDA approved drugs have not always been available for drug treatment. Prior to the use of these drugs, Alzheimer’s patients were commonly treated with WHAT forms of drugs to minimize their abnormal behavior?

What is Alzheimer’s disease (define)How are Nitrosamines formed? How can

nitrates and nitrites enter the body?

Homework Questions